Epigallocatechin gallate sensitizes cisplatin‐resistant oral cancer CAR cell apoptosis and autophagy through stimulating AKT/STAT3 pathway and suppressing multidrug resistance 1 signaling

• Published in: Environmental toxicology Vol. 32; no. 3; pp. 845 - 855
• Main Authors: Yuan, Chien‐Han, Horng, Chi‐Ting, Lee, Chiu‐Fang, Chiang, Ni‐Na, Tsai, Fuu‐Jen, Lu, Chi‐Cheng, Chiang, Jo‐Hua, Hsu, Yuan‐Man, Yang, Jai‐Sing, Chen, Fu‐An
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 01.03.2017
• Subjects: 4',6-diamidino-2-phenylindole; acridine orange; AKT/STAT3 signaling; antineoplastic activity; apoptosis; Apoptosis - drug effects; Apoptosis Regulatory Proteins - metabolism; ATP-Binding Cassette, Sub-Family B, Member 1 - genetics; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; autophagy; Autophagy - drug effects; Autophagy-Related Proteins - metabolism; Caspase 3 - metabolism; Caspase 9 - metabolism; caspase-3; caspase-9; Catechin - analogs & derivatives; Catechin - pharmacology; Cell Line, Tumor; cell viability; Cisplatin - pharmacology; Cisplatin - toxicity; cytotoxicity; Down-Regulation - drug effects; enzyme activity; epigallocatechin gallate; green fluorescent protein; green tea; Humans; MDR1; Microscopy, Fluorescence; mouth neoplasms; Mouth Neoplasms - metabolism; Mouth Neoplasms - pathology; multiple drug resistance; neoplasm cells; phosphorylation; Phosphorylation - drug effects; polyphenols; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; squamous cell carcinoma; staining; STAT3 Transcription Factor - metabolism; therapeutics; Western blotting; AKT/STAT3 signaling; apoptosis; MDR1; autophagy; epigallocatechin gallate
• ISSN: 1520-4081; 1522-7278; 1522-7278
• DOI: 10.1002/tox.22284

Epigallocatechin gallate (EGCG) is a green tea polyphenol that presents anticancer activities in multiple cancer cells, but no available report was addressed for the underling molecular mechanism of cytotoxic impacts on drug‐resistant oral squamous cell carcinoma cells. In the present study, the inhibitory effects of EGCG were experienced on cisplatin‐resistant oral cancer CAR cells. EGCG inhibited cell viability in a time‐ and concentration‐dependent manner by a sulforhodamine B (SRB) assay. EGCG induced CAR cell apoptosis and autophagy by 4′,6‐diamidino‐2‐phenylindole (DAPI) dye, acridine orange (AO) staining and green fluorescent protein (GFP)‐tagged LC3B assay, respectively. EGCG also significantly enhanced caspase‐9 and caspase‐3 activities by caspase activity assay. EGCG markedly increased the protein levels of Bax, cleaved caspase‐9, cleaved caspase‐3, Atg5, Atg7, Atg12, Beclin‐1, and LC3B‐II, as well as significantly decreased the expression of Bcl‐2, phosphorylated AKT (Ser473) and phosphorylation of STAT3 on Tyr705 by western blotting in CAR cells. Importantly, the protein and gene expression of multidrug resistance 1 (MDR1) were dose‐dependently inhibited by EGCG. Overall, downregulation of MDR1 levels and alterations of AKT/STAT3 signaling contributed to EGCG‐induced apoptosis and autophagy in CAR cells. Based on these results, EGCG has the potential for therapeutic effect on oral cancer and may be useful for long‐term oral cancer prevention in the future. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 845–855, 2017.